Supramolecular approaches for controlling the interactions between metal complexes and DNA
File(s)
Author(s)
Kench, Timothy
Type
Thesis
Abstract
G-Quadruplexes (G4) are a type of non-canonical DNA structure, formed from guanine-rich single-stranded DNA, which folds into a four-stranded structure of stacked tetrads. These highly stable structures have been shown to form in a range of physiological conditions and interest for G4 DNA as a target for anticancer therapeutics has increased dramatically as evidence for their existence in vivo has mounted. This is due to the identification of G4 forming sequences at the telomeres and in key oncogene promotor regions.
Much work has gone into the development of small molecules which can interact with G4 DNA, both as potential drugs to target disease and as new optical probes with which to continue to study G4 DNA. Our group is interested in the potential for metal complexes to be used as G4 binders; specifically, metal salphens. Pt(II)-salphens show excellent G4 stabilisation, are phosphorescent and have controllable redox states. This work therefore aimed to utilise Pt(II)-salphens as a tool for various applications. This has included the development of emissive dimeric ligand systems which can be used to selectively target higher order G4 DNA structures potentially found at the telomeres.
We have also developed several approaches aimed at caging Pt(II)-salphens for triggered release. The first of these involved the synthesis of a set of interlocked compounds (rotaxanes) with cleavable stopper groups. When enclosed, the Pt(II)-salphen could not interact with DNA. Upon exposure to either light an enzyme the rotaxanes broke down, releasing the Pt(II)-salphen. Both the cytotoxicity and cellular localisation of the rotaxanes could be controlled via this mechanism.
Finally, a series of redox controlled PtIV-salphens with improved stability were synthesised. These compounds were based on an inactive form of a PtII-salphen, which is activated by bio-reductants found in higher concentrations in tumour environments.
Much work has gone into the development of small molecules which can interact with G4 DNA, both as potential drugs to target disease and as new optical probes with which to continue to study G4 DNA. Our group is interested in the potential for metal complexes to be used as G4 binders; specifically, metal salphens. Pt(II)-salphens show excellent G4 stabilisation, are phosphorescent and have controllable redox states. This work therefore aimed to utilise Pt(II)-salphens as a tool for various applications. This has included the development of emissive dimeric ligand systems which can be used to selectively target higher order G4 DNA structures potentially found at the telomeres.
We have also developed several approaches aimed at caging Pt(II)-salphens for triggered release. The first of these involved the synthesis of a set of interlocked compounds (rotaxanes) with cleavable stopper groups. When enclosed, the Pt(II)-salphen could not interact with DNA. Upon exposure to either light an enzyme the rotaxanes broke down, releasing the Pt(II)-salphen. Both the cytotoxicity and cellular localisation of the rotaxanes could be controlled via this mechanism.
Finally, a series of redox controlled PtIV-salphens with improved stability were synthesised. These compounds were based on an inactive form of a PtII-salphen, which is activated by bio-reductants found in higher concentrations in tumour environments.
Version
Open Access
Date Issued
2021-09
Date Awarded
2022-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Vilar Compte, Ramon
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)